CN109081812A - 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate - Google Patents
4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The present invention relates to the monohydrates (compound shown in formula 2) and its preparation method and application of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester.The compound can by can be miscible with water organic solvent, such as the in the mixed solvent of acetone and water crystallizes to obtain.The purity is high of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate that the present invention obtains, yield are also high, to be conducive to the synthesis of subsequent olmesartan medoxomil.
Description
Technical field
The present invention relates to chemical fields；Specifically, the present invention relates to noval chemical compound, 4- (1- hydroxyl -1- Methylethyl) -
2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate and its preparation method and application.
Background technique
4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester (formula 1) is the pass for synthesizing olmesartan medoxomil
Key intermediate.J.Med.Chem.1996,39,323-338 report its synthetic method earliest, and this method is with 2- propyl imidazole -4,5-
Ethyl dicarboxylate's (formula 3) is that raw material reacts in ether with methylmagnesium-bromide, then is acidified with saturated aqueous ammonium chloride, acetic acid second
Ester extraction after organic solvent is evaporated off, is recrystallized with isopropyl ether-n-hexane mixed solvent, compound of formula I is made, and yield is
95%, the purity data of compound of formula I of not registering in text.
Chinese patent application 200710040938.6 discovery using methylmagnesium-chloride substitution document (J.Med.Chem.1996,
39,323-338) methylmagnesium-bromide in carries out grignard reaction, can reduce ether impurity (impurity 4) and olefinic impurity (impurity in reaction
5) generation.
The discovery of Chinese patent application 2014106577050 uses methylmagnesium-chloride, molten in the mixing of toluene and tetrahydrofuran
Under reacting in agent, less impurity 6 is produced.
Above 2 Chinese patent applications are by controls such as reagent, the solvents of reaction so that in reaction process as far as possible
Impurity 4, impurity 5 and impurity 6 are generated less.
However, the above method is to reduce to generate in 1 compound of formula synthesis process itself by optimum synthesis technique
Impurity, to improve the purity of 1 compound of formula.There is still a need for other more easy technological means for this field to obtain high-purity,
Such as purity is higher than > 99.0% 1 compound of formula, to be conducive to the synthesis of subsequent olmesartan medoxomil.
Summary of the invention
The purpose of the present invention is to provide the 4- of high-purity (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid second
Ester.
Another object of the present invention is to provide a kind of novel 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5-
Carboxylic acid, ethyl ester monohydrate (2 compound of formula).
In a first aspect, the present invention provides a kind of preparation method of compound shown in formula 2, the method includes following steps
It is rapid:
1) compound shown in formula 1 is dissolved in the in the mixed solvent of organic solvent and water that can be miscible with water；
2) the resulting solution of step 1) is cooled to certain crystallization temperature, to precipitate crystal；With
3) filtration step 2) be precipitated crystal, to obtain compound shown in formula 2；
In a particular embodiment, the mixed solvent packet of organic solvent and water that can be miscible with water described in step 1)
Include but be not limited to acetone/water mixed solvent, ethanol/water mixed solvent and methanol/water mixed solvent；It is preferred that acetone/water mixing is molten
Agent.
In a particular embodiment, the ratio of the acetone/water mixed solvent is acetone: water=1:2~1:4 (v:v)；
It is preferred that 1:3~1:4 (v:v)；Most preferably 1:3 (v:v).
In a particular embodiment, crystallization temperature described in step 2) is -25~20 DEG C；It is preferred that -25~10 DEG C；Most
It is preferred that -10~10 DEG C.
In a preferred embodiment, 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester one is hydrated
The purity of object can achieve 99% or more, more preferable 99.5%.
In a preferred embodiment, 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester one is hydrated
The yield of object can achieve 75% or more, 80% or more, even 85% or more.
In second aspect, the present invention provides compound shown in formula 2:
In a particular embodiment, the powder x-ray diffraction map of the compound has feature at following 2 θ value
Peak: 12.15 ± 0.1,13.55 ± 0.1,13.81 ± 0.1,20.99 ± 0.1.
In a particular embodiment, the powder x-ray diffraction map of the compound further includes at following 2 θ value
Characteristic peak: 9.69 ± 0.1,19.93 ± 0.1,20.12 ± 0.1.
In a particular embodiment, the powder x-ray diffraction map of the compound has feature at following 2 θ value
Peak: 6.00 ± 0.1,7.54 ± 0.1,8.13 ± 0.1,9.69 ± 0.1,12.15 ± 0.1,13.08 ± 0.1,13.55 ± 0.1,
13.81±0.1、15.43±0.1、18.31±0.1、19.06±0.1、19.93±0.1、20.12±0.1、20.99±0.1、
22.22±0.1、23.76±0.1、26.40±0.1、27.41±0.1、30.51±0.1、31.81±0.1。
In a particular embodiment, the powder x-ray diffraction map of the compound is substantially as shown in Figure 4.
In a preferred embodiment, compound shown in formula 2 is prepared by preparation method described in first aspect.
In the third present invention, the present invention provides the purposes of compound shown in formula 2 described in second aspect, is used to prepare Aomei
Husky smooth ester.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows the molecule stereo structure ellipsoid figure that the Advances in crystal X-ray diffraction map of 2 compound of formula obtains；
The structure cell along c-axis direction that Fig. 2 shows that the Advances in crystal X-ray diffraction of 2 compound of formula obtains accumulates perspective view；
Fig. 3 shows the 2 compound powder X-ray diffraction theory map of formula derived by 2 compound monocrystal of formula；
Fig. 4 shows the powder x-ray diffraction map of 2 compound of formula of actual measurement；
Fig. 5 shows the powder x-ray diffraction spectrum data of 2 compound of formula of actual measurement；
Fig. 6 shows the powder x-ray diffraction map of 1 compound of formula of actual measurement；
Fig. 7 shows the powder x-ray diffraction spectrum data of 1 compound of formula of actual measurement；
Fig. 8 shows the powder X-ray-of the powder x-ray diffraction map of 1 compound of formula of actual measurement and 2 compound of formula of actual measurement
The comparison map of x ray diffraction map；Wherein 1 compound of formula corresponds to a curve topmost, and two of 2 compound of formula criticize
Secondary following two curves of correspondence；
Fig. 9 shows the molecule stereo structure figure that the Advances in crystal X-ray diffraction map of 8 compound of formula obtains.
Specific embodiment
After extensive and in-depth study, inventor is to 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic
During acetoacetic ester is crystallized, it was unexpectedly found that utilizing the available 4- of specific mixed solvent (1- hydroxyl -1- first
Base ethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate, obtained 4- (1- hydroxyl -1- Methylethyl) -2- propyl miaow
The purity is high of azoles -5- carboxylic acid, ethyl ester monohydrate, thus highly beneficial to the synthesis of subsequent olmesartan medoxomil.It is complete on this basis
At the present invention.
4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate
Herein, " 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate " or " formula 2
Shown compound " has the same meaning.The two each means structural formula compound as shown in Equation 2, that is, 1 molecule 4- (1- hydroxyl
Base -1- Methylethyl) hydrate that constitutes of -2- propyl imidazole -5- carboxylic acid, ethyl ester (compound shown in formula 1) and 1 molecular water
The present inventor has found in the research process to the synthesis technology of olmesartan medoxomil, the key intermediate of high-purity,
The acquisition of 2- propyl imidazole -4,5- ethyl dicarboxylate (compound shown in formula 1) is extremely difficult.To obtain shown in the formula 1 of high-purity
Compound needs to carry out repeated recrystallize using acetonitrile, because impurity 4, impurity 5, the structure of impurity 6 and 1 compounds of formula are seemingly,
Recrystallization is difficult to remove them.In order to improve the purity of 1 compound of formula from 95% to 99.0%, at least acetonitrile is needed to tie again
It is 2 times brilliant.And the yield of single recrystallization is about 70%, recrystallizing yield twice is about 48%, to cause in recrystallization process
Product loss is more than half.However, often obtaining the grease of syrupy shape if do not recrystallized using acetonitrile, grease exists
Slowly (2~3 week) solidification obtains 1 compound of solid type in placement process.So operation, it is not only time-consuming very long, after crystallization
Purity is not also high.Therefore, want that 1 compound of solid type for obtaining high-purity (> 99.0%) is extremely difficult in the prior art.
For the crystallization purifying for solving the problems, such as 1 compound of formula, the present invention provides a kind of solid 4- (1- hydroxyls for preparing high-purity
Base -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester new method, the core of the new method is when using miscible with water
Organic solvent, such as when the mixed solvent of acetone and water recrystallizes 1 compound of formula, unexpectedly obtain 1 chemical combination of formula
The monohydrate of object, that is, compound shown in formula 2
Research discovery before the present inventor: similar with 1 compound structure of formula and be similarly in Olmesartan Lipase absobed
What 7 compound of imidazoles formula of mesosome was recrystallized to give in acetone/water in the mixed solvent is 8 compound of formula, that is, formula 7 is changed
Close the acetone solvate (as follows) of object.
8 compound of formula has carried out structural identification by Advances in crystal X-ray diffraction map, and the single crystal X-ray of 8 compound of formula spreads out
It penetrates map and sees Fig. 9.The Advances in crystal X-ray diffraction spectrum data of 8 compound of formula is as follows.
Crystal data:
C43H38N6O2·C3H6O；Mr=728.87；Triclinic,P-1
α=95.806 (13) °
β=92.547 (14) °
γ=102.015 (13) °
Z=2；Mo Kαradiation；μ=0.077mm-1；T=293K；colourless；
0.40x0.20x0.20mm。
Based on 7 compound of formula obtain 8 compound of formula as a result, according to conventional imagination, when similarly using acetone and water
Mixed solvent when being recrystallized to 1 compound of formula, it should obtain compound shown in formula 9, that is, the acetone of 1 compound of formula is molten
Object (as follows) is closed in agent.
However, actual conditions are but far from it, when the in the mixed solvent of acetone/water is recrystallized, from 1 compound of formula
What is obtained is not that acetone closes object but monohydrate, that is, compound shown in formula 2 (as follows).
The acquisition of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate (formula 2) is to exceed
Expect, structure is confirmed by the Advances in crystal X-ray diffraction map of such as Fig. 1 and Fig. 2, and key mapping also can be seen into from Fig. 2
The oxygen atom on the hydroxyl for being hydrogen atom in hydrone and 2 compound of formula is set into Hydrogenbond.
The Advances in crystal X-ray diffraction spectrum data of 2 compound of formula is as follows.
The identification of 2 compound of formula: the powder x-ray diffraction theory map obtained by the monocrystalline theory deduction of 2 compound of formula
As shown in Figure 3.Fig. 4 is the actual measurement powder x-ray diffraction map of 2 compound of formula.Comparing Fig. 3 and Fig. 4 can see, the two
Powder x-ray diffraction map is consistent, and 2 θ values of powder x-ray diffraction map are identical.Therefore also confirm mixed by acetone/water
2 compound of formula that bonding solvent crystallizes is exactly the compound in monocrystalline.
The actual measurement powder x-ray diffraction map of 2 compound of formula is as shown in figure 4, survey the number of powder x-ray diffraction map
According to as shown in Figure 5.There it can be seen that the powder x-ray diffraction map of 2 compound of formula has characteristic peak at following 2 θ value:
12.15±0.1,13.55±0.1,13.81±0.1,20.99±0.1；In a preferred embodiment, the powder of 2 compound of formula
Last X-ray diffracting spectrum further includes the characteristic peak at following 2 θ value: 9.69 ± 0.1,19.93 ± 0.1,20.12 ± 0.1；?
In most preferred embodiment, the powder x-ray diffraction map of 2 compound of formula is at following 2 θ value with characteristic peak: 6.00 ±
0.1、7.54±0.1、8.13±0.1、9.69±0.1、12.15±0.1、13.08±0.1、13.55±0.1、13.81±
0.1、15.43±0.1、18.31±0.1、19.06±0.1、19.93±0.1、20.12±0.1、20.99±0.1、22.22±
0.1、23.76±0.1、26.40±0.1、27.41±0.1、30.51±0.1、31.81±0.1。
The powder x-ray diffraction map of 1 compound of formula as shown in fig. 6, its actual measurement powder x-ray diffraction spectrum data
As shown in Figure 7.Its powder x-ray diffraction map 2 θ values be 8.34 ± 0.1,8.68 ± 0.1,9.03 ± 0.1,11.91 ±
0.1、12.82±0.1、13.00±0.1、13.89±0.1、14.48±0.1、12.59±0.1、16.89±0.1、18.21±
0.1、19.21±0.1、22.04±0.1、22.37±0.1、22.61±0.1、22.87±0.1、23.86±0.1、24.25±
0.1, there is at 25.67 ± 0.1,28.10 ± 0.1 characteristic peak.
The identification respectively of 1 compound of formula and 2 compound of formula: powder x-ray diffraction map such as Fig. 6 institute of 1 compound of formula
Show, the powder x-ray diffraction map of 2 compound of formula as shown in figure 4, the comparison map of the two as shown in figure 8, as can be seen that two
There is very big difference in the powder x-ray diffraction map of person.One curve in the top Fig. 6 is the actual measurement powder X-ray-of 1 compound of formula
X ray diffraction map, below two curves be two different batches 2 compound of formula actual measurement powder x-ray diffraction map, formula
1 and the powder x-ray diffraction map of 2 compound of formula there are significantly different.Therefore it can be incited somebody to action by powder x-ray diffraction map
1 compound of formula is identified and is distinguished with 2 compound of formula.
Well known to those skilled in the art, can a certain compound become solvate in conjunction with solvent or combine several molecules molten
Agent, it is not regular to follow.As described above, 7 compound of formula crystallizes in acetone/water, obtain is that acetone closes object (formula 8), and is tied
It is monohydrate (formula 2) that similar 1 compound of formula of structure crystallizes obtain in acetone/water；Some one molecules of compound may be used also
To combine a few molecule solvent molecules, such as cupric sulfate pentahydrate, green-vitriol.
1 compound of discoverable type can form the characteristic of a molecular crystalline water to the present inventor with water for the first time, obtain new one
Hydrate (formula 2), and purified using the characteristic.1 compound of formula can form monohydrate and be precipitated from solvent, and impurity
Hydrate cannot be formed, to be not precipitated from solvent substantially, the purity of the monohydrate because obtained from it is especially high (>
99.0%), and recrystallize yield also very high (> 85%).
The crystallization water is removed by heat drying, high-purity can be obtained from 2 compound of high-purity formula that the present invention obtains
1 compound of formula.The high-purity type I compound that 2 compound of formula obtains after drying can also be by powder x-ray diffraction map
It is confirmed, powder x-ray diffraction map is consistent with Fig. 6.
The preparation method of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate
The present inventor has found for the first time, 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester can with
The in the mixed solvent for the organic solvent and water that water dissolves each other recrystallizes, to obtain specific 4- (1- hydroxyl -1- Methylethyl) -2-
The monohydrate of propyl imidazole -5- carboxylic acid, ethyl ester.
Based on the teachings of the present invention, those skilled in the art could be aware that organic solvent tool miscible with water as described herein
Which kind of organic solvent body is.In a particular embodiment, the organic solvent miscible with water used in the present invention includes but unlimited
In acetone, ethyl alcohol and methanol.In a preferred embodiment, the organic solvent miscible with water used in the present invention is acetone.
As known to those skilled in the art, in recrystallization process the conditions such as ratio and operation temperature of solvent for recrystallization
As a result, for example yield also has unexpected influence.For example, solubility increases sodium chloride when the temperature rises, and hydrogen-oxygen
Solubility declines instead when the temperature rises for change calcium and calcium carbonate.Therefore, the present inventor further grasps recrystallization of the invention
Each technological parameter in work is groped.
The inventors discovered that when organic solvent miscible with water, such as the ratio of acetone and water is 1:2~1:4 (v:v)；
It is preferred that when 1:3~1:4, when most preferably 1:3, recrystallizes yield highest, and effect is best.
When crystallization temperature is -25~20 DEG C, good recrystallization yield can be obtained；And when crystallization temperature be -25~
10 DEG C, when most preferably crystallization temperature is -10~10 DEG C, recrystallize yield highest.
Advantages of the present invention:
1. the hydration that the present invention obtains 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester for the first time
Object, to be conducive to the synthesis of subsequent olmesartan medoxomil；
2. the side that the present invention obtains the monohydrate of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester
Method is easy to operate, at low cost, environmental-friendly；
3. 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate that the present invention obtains is pure
Degree is high, can achieve 99% or more or even 99.5% or more；
4. the yield of 4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate that invention obtains
Height can achieve 775% or more, 80% or more, even 85% or more.
Technical solution of the present invention is further described below in conjunction with specific implementation case, but following case study on implementation is not constituted
Limitation of the present invention, the various method of administration that all principles and technological means according to the present invention use, belongs to the present invention
Range.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or is built according to manufacturer
The condition of view.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment
The preparation of embodiment 1:4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester (1 compound of formula)
50.0 grams of (2.08mol) magnesium powders are added in 3L reaction flask, 1000ml tetrahydrofuran is heated to flowing back, and keeps molten
Liquid is slightly boiled, leads to methyl chloride gas with the speed of 200ml/min, magnesium powder stops ventilation after disappearing, it is molten that grey methylmagnesium-chloride is made
Liquid.132.4 grams of (0.52mol) 2- propyl imidazole -4,5- ethyl dicarboxylates (formula 3) are dissolved in 1000ml tetrahydrofuran, in 60
It DEG C is added dropwise in methyl chloride magnesium solution, drop finishes, and continues stirring 2 hours.Evaporating solvent under reduced pressure.It is cooled to room temperature.It is added dropwise 10%
Hydrochloric acid solution is to pH=5.Ethyl acetate 1000ml is added to extract, water layer uses ethyl acetate 200ml × 2 to extract again, organic laminated
And washed afterwards with 200ml saturated common salt, magnesium sulfate dries, filters, and filtrate decompression is evaporated off solvent and obtains 124.1 grams of 4- (1- hydroxyl -1-
Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester (formula 1) crude product (HPLC purity 95.0%).
10.0 grams of crude products are taken, with 100ml recrystallized from acetonitrile, obtain primary crystallization solid, a knot solid is not dried, then is used
100ml recrystallized from acetonitrile, the solid was filtered, be dried in vacuo in 60 DEG C 4.81 grams of 1 compounds of secondary crystallization solid type (HPLC is pure
Degree is 99.1%).
1 compound powder X-ray diffraction of secondary crystallization solid type test map is shown in Fig. 6, and data are shown in Fig. 7.
HPLC method: C18 column；Acetonitrile: 10mMKH2PO4 (pH 3.0)=20:80；25 DEG C of column temperature；Detection wavelength 254nm；
Flow velocity 1.0ml/min；Sample concentration 2mg/ml, 10 μ l of sampling volume；1 Compound Retention time 7min of formula.
Embodiment 2:4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate (2 chemical combination of formula
Object) preparation
10.0g 4- (1- hydroxyl-l- Methylethyl) -2- propyl imidazole -5- ethyl acetate (formula 1) crude product (HPLC purity
95.0%) it is added into 10ml acetone, is heated to dissolving, 30ml water is slowly added dropwise under stirring.Ice salt bath is cooled to -5 DEG C, heat preservation
It is stirred for 3 hours.Filtering, filter cake are washed with 10ml acetone/water (1:3), are obtained 10.5g 4- (1- hydroxyl -1- Methylethyl) -
The Off-white solid of 2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate (formula 2), HPLC purity 99.5%.2 compound powder X- of formula
X ray diffraction test map is shown in Fig. 4, and data are shown in Fig. 5.
Embodiment 3: by 1 compound of formula of 2 compound of the formula preparation high-purity of high-purity
2 compound of formula (HPLC purity 99.5%) obtained in embodiment 2, which is set in vacuum drying oven, to be dried under reduced pressure to perseverance for 50 DEG C
Weight obtains 1 compound of formula of 8.5g no crystal water, recrystallizes yield 85%, HPLC purity 99.5%, powder x-ray diffraction test
Map is consistent with Fig. 6.
Embodiment 4:4- (1- hydroxyl -1- Methylethyl) -2- propyl imidazole -5- carboxylic acid, ethyl ester monohydrate (2 chemical combination of formula
Object) monocrystalline preparation
Take 0.1g 4- (1- hydroxyl-l- Methylethyl) -2- propyl imidazole -5- ethyl acetate (formula 1) plus 3ml acetone/water
(1:3) is heated to dissolving, and Slow cooling crystallization obtains 2 compound monocrystal of formula, carries out Advances in crystal X-ray diffraction test, map such as Fig. 1,
Shown in Fig. 2.
Embodiment 5: the comparative experiments of different recrystallization solvents
Present invention firstly discovers that 1 compound of formula monohydrate, be to crystallize to obtain from the in the mixed solvent of acetone/water,
Whether the mixed solvent recrystallization of other solvents miscible with water and water composition can also obtain monohydrate, and the present inventor also carries out
Experiment.
4 three-necked bottles are taken, 10.0 grams of 4- (1- hydroxyl-l- Methylethyl) -2- propyl imidazole-is added in each three-necked bottle
5- ethyl acetate (formula 1) crude product (HPLC purity 95.0%), is separately added into 10ml acetone, 10ml ethyl alcohol, 10ml methanol, 10ml bis-
It in first sulfoxide, is heated to dissolving, 40ml water is slowly added dropwise in each three-necked bottle under stirring.Ice salt bath is cooled to -5 DEG C, and heat preservation is stirred again
It mixes 3 hours.Filtering, the solid of acquisition, the test of delivering powder X-ray diffraction judge whether it is monohydrate with Fig. 4 comparison, as a result
Such as following table.The solid of acquisition is set in vacuum drying oven and is dried under reduced pressure to constant weight for 50 DEG C, and recrystallization yield and purity are calculated, as a result as follows
Table.
| Recrystallization solvent type | Solvent: water (v:v) | It whether is monohydrate | Recrystallize yield | HPLC purity |
| Acetone/water | 1:4 | It is | 88% | 99.5% |
| Ethanol/water | 1:4 | It is | 80% | 99.1% |
| Methanol/water | 1:4 | It is | 75% | 99.2% |
| Dimethyl sulfoxide/water | 1:4 | It is no | 60% | 94.2% |
Experiment discovery: acetone/water, ethanol/water, methanol/water can be obtained the monohydrate of 1 compound of formula, and dimethyl sulfoxide/
The monohydrate of 1 compound of formula is not obtained in water.As it can be seen that and not all solvent miscible with water and water composition mixed solvent
The monohydrate that can obtain 1 compound of formula is recrystallized to formula 1.
Compare acetone/water, ethanol/water, methanol/water and has obtained 2 compound of formula (1 monohydrate of formula), what acetone/water obtained
2 compound form of formula is big, easily filtering, and to obtain 2 compound of formula tacky for ethanol/water, methanol/water, is not easy to filter.From recrystallization
It is seen on yield, it is higher that acetone/water recrystallizes yield.It is preferred that acetone/water mixed solvent recrystallizes.
Embodiment 6: the comparative experiments of different crystallization temperature recrystallizations
Due to the different solubility of different temperatures, there is very big influence to the yield of crystallization in temperature.The present inventor changes formula 2
Closing object, crystallization yield is investigated at different temperatures.
4 three-necked bottles are taken, 10.0 grams of 4- (1- hydroxyl-l- Methylethyl) -2- propyl imidazole-is added in each three-necked bottle
5- ethyl acetate (formula 1) crude product (HPLC purity 95.0%), 10ml acetone.It is heated to dissolving, each three-necked bottle is slow under stirring
30ml water is added dropwise.It is cooled to 10~20 DEG C, 0~10 DEG C, -10~0 DEG C, -25~-10 DEG C respectively, heat preservation is stirred for 3 hours.It crosses
Filter, the solid of acquisition, the test of delivering powder X-ray diffraction judge whether it is monohydrate with the comparison of attached drawing 4, as a result such as following table.
The solid of acquisition is set in vacuum drying oven and is dried under reduced pressure to constant weight for 50 DEG C, recrystallization yield is calculated, as a result such as following table.
From experimental result as it can be seen that compared with the yield recrystallized in the prior art using acetonitrile to 1 compound of formula, this
The method of invention is fine in -25~20 DEG C of yield, but when crystallization temperature is -25~10 DEG C, especially -10~10 DEG C
When, yield highest is recrystallized, effect is best.
Embodiment 7: the comparative experiments of different water consumption recrystallizations
The present inventor further studies the ratio of acetone/water mixed solvent.
5 three-necked bottles are taken, 10.0 grams of 4- (1- hydroxyl-l- Methylethyl) -2- propyl imidazole-is added in each three-necked bottle
5- ethyl acetate (formula 1) crude product (HPLC purity 95.0%), 10ml acetone.It is heated to dissolving, it is slow in three-necked bottle respectively under stirring
It is slow that 10ml water, 20ml water, 30ml water, 40ml water, 50ml water is added dropwise.It is cooled to -5~0 DEG C, heat preservation is stirred for 3 hours.Filtering,
The solid of acquisition, the test of delivering powder X-ray diffraction judge whether it is monohydrate with the comparison of attached drawing 4, as a result such as following table.It obtains
Solid set in vacuum drying oven 50 DEG C and be dried under reduced pressure to constant weight, recrystallization yield is calculated, as a result such as following table.
| Acetone: water (v:v) | It whether is monohydrate | Recrystallize yield |
| 1:1 | It is | 60% |
| 1:2 | It is | 85% |
| 1:3 | It is | 89% |
| 1:4 | It is | 88% |
| 1:5 | It is | 80% |
From experimental result as it can be seen that the ratio of acetone/water mixed solvent is acetone: water=1:2~1:4 (v:v)；More preferably exist
1:3~1:4 (v:v)；Recrystallization yield highest when especially 1:3 (v:v), effect are best.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of preparation method of compound shown in formula 2, the described method comprises the following steps:
1) compound shown in formula 1 is dissolved in the in the mixed solvent of organic solvent and water that can be miscible with water；
2) the resulting solution of step 1) is cooled to certain crystallization temperature, to precipitate crystal；With
3) filtration step 2) be precipitated crystal, to obtain compound shown in formula 2；
2. preparation method as described in claim 1, which is characterized in that organic solvent that can be miscible with water described in step 1)
Mixed solvent with water includes but is not limited to acetone/water mixed solvent, ethanol/water mixed solvent and methanol/water mixed solvent；It is excellent
Select acetone/water mixed solvent.
3. preparation method as claimed in claim 2, which is characterized in that the ratio of the acetone/water mixed solvent is acetone: water
=1:2~1:4 (v:v)；It is preferred that 1:3~1:4 (v:v)；Most preferably 1:3 (v:v).
4. preparation method as described in claim 1, which is characterized in that crystallization temperature described in step 2) is -25~20 DEG C；
It is preferred that -25~10 DEG C；Most preferably -10~10 DEG C.
5. compound shown in formula 2:
6. compound shown in formula 2 as claimed in claim 5, which is characterized in that the powder x-ray diffraction figure of the compound
Spectrum is at following 2 θ value with characteristic peak: 12.15 ± 0.1,13.55 ± 0.1,13.81 ± 0.1,20.99 ± 0.1.
7. compound shown in formula 2 as claimed in claim 6, which is characterized in that the powder x-ray diffraction figure of the compound
Spectrum further includes the characteristic peak at following 2 θ value: 9.69 ± 0.1,19.93 ± 0.1,20.12 ± 0.1.
8. compound shown in formula 2 as claimed in claim 5, which is characterized in that the powder x-ray diffraction figure of the compound
Spectrum has characteristic peak at following 2 θ value: 6.00 ± 0.1,7.54 ± 0.1,8.13 ± 0.1,9.69 ± 0.1,12.15 ± 0.1,
13.08±0.1、13.55±0.1、13.81±0.1、15.43±0.1、18.31±0.1、19.06±0.1、19.93±0.1、
20.12±0.1、20.99±0.1、22.22±0.1、23.76±0.1、26.40±0.1、27.41±0.1、30.51±0.1、
31.81±0.1。
9. compound shown in formula 2 as claimed in claim 5, which is characterized in that the powder x-ray diffraction figure of the compound
It composes substantially as shown in Figure 4.
10. the purposes of compound shown in formula 2 described in any one of claim 5-9, is used to prepare olmesartan medoxomil.
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| CN201811003933.0A CN109081812B (en) | 2018-08-30 | 2018-08-30 | 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid ethyl ester monohydrate |
| PCT/CN2019/102360 WO2020043025A1 (en) | 2018-08-30 | 2019-08-23 | Hydrate of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester |
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